Peanut allergy is common, with recent studies estimating a prevalence of 0.8% in children and an overall prevalence of 0.5% - 1% in the general population, and there is evidence that the prevalence of peanut allergy is rising in both the United States and Europe. Currently, the only treatment for peanut allergy is a peanut-free diet and ready access to self-injectable epinephrine. However, accidental ingestions are common, with up to 50% of food-allergic patients having an allergic reaction over a two-year period. Allergic reactions to peanut can be severe and life threatening, with peanut and/or tree nut allergies accounting for the vast majority of fatal food-induced anaphylaxis. Given these facts, the development of effective therapy for peanut allergy is critical. Over the past several years we have made substantial progress in our understanding of peanut allergy and potential treatment strategies for peanut and other food allergies. Recent studies have shown the potential of oral immunotherapy for the treatment of milk, egg and peanut allergies, but this therapy primarily appears to induce desensitization, and adverse reactions are common, unpredictable and sometimes severe. Consequently, more effective therapies are needed. The goal of this application is to expand upon these preliminary studies to determine which treatment modality is likely to be most effective and potentially applicable to the general population of peanut allergic patients, and to understand the immunologic mechanisms associated with the development of desensitization and tolerance induced by these immunotherapeutic modalifies. We will accomplish this by pursuing the following Specific Aims: (1) confinue the ongoing trial of peanut sublingual immunotherapy (SLIT) initiated in CoFAR 1; (2) implement a Phase l/ll trial of a novel therapeufic compound, EMP-123, based on the results of our ongoing Phase I trial in CoFAR 1; (3) initiate a trial of a novel epicutaneous immunotherapy (EPIT) for the treatment of peanut allergy; and (4) invesfigate the similarities and differences between these approaches through the use of novel mechanisfic studies. In the 3 therapeufic trials, we will study the clinical and immunologic effects of these therapies, determine their potenfial to induce long-term tolerance, and assess their safety profiles. By introducing peanut allergens to the immune system by different routes, i.e. oral mucosa, epidermis, and rectal mucosa [with innate immune activators], we anticipate different host responses that will induce desensitizafion and eventually tolerance. The mechanisfic studies planned should provide new insight into the inducfion of tolerance in IgE-mediated food allergy.